This invention relates to a tablet excipient, and in particular, to a starch binder and/or filler useful in manufacturing tablets, pellets, capsules or granules for the delivery of drugs, chemicals or other active agents. The tablet excipient is prepared by the enzymatic debranching of starch containing greater than 90% amylopectin with an alpha-1,6-D-glucanohydrolase to yield at least 20%, by weight, short chain amylose. The starch may be highly or partially debranched and may comprise amylopectin, partially debranched amylopectin, or a combination thereof, in addition to the short chain amylose and will be substantially free of long chain amylose.
Tablets and capsules usually consist of several inert materials, referred to as excipients, in addition to the active ingredient which is present in amounts sufficient to accomplish the desired pharmaceutical, nutritive, or chemical effect. These excipients are generally classified according to their functions, such as diluents (also called bulking agents and fillers), binders which hold the ingredients together, and binder-diluents which perform both functions. Tablets may also contain disintegrants which help the tablet to break apart and release the active ingredient when placed in a fluid environment, lubricants to improve the release of the compressed tablet from the die and punches, glidants to improve the flow, and anti-adhesives to prevent film formation on the punches. Other optional ingredients may be moisture absorbants, surface gloss and/or hardness agents, dyes, flavors, sweeteners, antioxidants and/or sorbents.
Different properties are required from starch used as a binder and starch used as a disintegrant. The most important property required in a binder is compressibility. Granular starches and conventional pregelatinized starches (i.e., cooked and cold-water-dispersible) do not bind well under direct compression.
Tabletting and some capsule-filling operations are based on the ability of certain powders to bind under compression. Compressed tablets may be prepared by wet granulation, dry granulation (e.g., slugging), or direct compression. Common dry dosage capsule-filling operations make use of a material that can be gravity- or force-fed into the capsule or a material that can be formed into a plug which is then used to fill the capsule. For the former, a material which improves the flow properties of the powder mix is desirable. For the latter, a binder-diluent which is easily compressed under low pressure to form a soft plug is required. Because different functional properties are required for these different operations, a starch-based excipient may not be useful in all operations or may serve different purposes in different operations.
The steps involved in a typical wet granulation include mixing the components, preparing the granulating binder solution, thoroughly mixing the components with the granulating binder solution to form a dough, coarse screening the moist mass through a sieve, drying, grinding, adding the lubricant, and compressing the tablets.
The steps involved in slugging are mixing the powdered components, compressing the mixture into hard slugs, grinding the slugs to the desired particle size, screening, adding the other excipients, and compressing the mixture into tablets.
The most preferred and economical tabletting method, direct compression, requires only two steps-mixing the dry components and compressing the mixture into tablets.
The binders or binder-diluents used in the above tabletting or capsule-filling operations should be stable, non-reactive and non-hygroscopic, free-flowing powders with some compressibility. The binders used for direct compression tabletting require excellent binding properties.
Typical wet granulation binders include starch pastes, conventional pregelatinized starches, gelatin, polyvinylpyrrolidone, methyl cellulose, sucrose, dextrose, and natural gums.
Conventional starch binders such as pregelatinized, modified and stabilized waxy maize starch, pregelatinized corn starch, pregelatinized tapioca or potato starch, stable modified amylopectin, low viscosity tapioca dextrin, dextrinized corn starch and/or cold-water-swelling pregelatinized corn starch, which are water-soluble and have limited, if any, direct compression properties, typically are not used in direct compression tabletting, but are suitable for wet granulation. Such wet granulation binders may be used in a blend wherein another binder(s) provides direct compressibility. Such blends are useful in hybrid wet granulation-direct compression tabletting processes.
Typical direct compression binders include microcrystalline cellulose, compressible sugars, specific calcium salts, lactose, and dextrose. Of these, microcrystalline cellulose is the preferred binder and it also displays good disintegration properties. However, tablets made with this binder tend to have dull rough surfaces. Also microcrystalline cellulose is very expensive. Other preferred binders include the calcium phosphates (di- or tribasic) and compressible sugars, but each has its disadvantage. Namely, the calcium salts do not allow one to prepare tablets with a high level of active ingredient and generally require the use of disintegrants. The sugars (mostly made up of sucrose) present a darkening problem, tend to increase in hardness with age, and may react with drugs. Lactose has limited binding properties and exhibits a browning reaction when exposed to heat and moisture; it also requires the use of a disintegrant. Mannitol and sorbitol have certain taste advantages but either lack binding properties and require a disintegrant or are too hygroscopic or too expensive.
Physically modified, partially cold-water-swelling, cold-water-soluble compacted starches are reportedly useful as binder-disintegrants for direct compression tabletting (see U.S. Pat. Nos. 3,622,677 and 4,072,535 issued Nov. 23, 1971 and Feb. 7, 1978 to R. W. Short, et al.) and as free-flowing fillers for dry dosage capsules (see U.S. Pat. No. 4,072,535 cited above). The modification, which is carried out by passing the starch through closely spaced steel rollers with or without the use of supplemental thermal energy, disrupts and fractures at least some of the granules and results in a mixture of birefringent and non-birefringent granules and fragments, as well as completely solubilized starch (typically about 10-20%). The compacted mass is ground and classified into particle size fractions. The resulting starch does have limited direct compression binding but the loading potential is low and the use of an auxiliary binder is often required.
Hydrolyzed starches, such as dextrinized starches having a dextrose equivalent of from about 0.5-50, are used as "melting point elevators" in a hybrid wet granulation-direct compression tabletting process for preparing nonfriable, rapidly water-soluble tablets such as sweetened or unsweetened beverage tablets (see U.S. Pat. No. 4,384,005 issued May 17, 1983 to D. R. McSweeney). An aqueous moistener comprising corn syrup and optionally glycerine is added to the dry mix containing the acidulant and optional components, and the hydrolyzed starch is added in an amount sufficient to function as a melting point elevator and also to convert the moistened mixture into a free-flowing mixture suitable for direct compression. The melting point elevator raises the melting point of the mixture so that the tablet will not soften, melt or form a hard core during the optional drying step that follows tablet formation.
Starch fractions, such as non-granular amylose, are also reportedly useful as binder-disintegrants in direct compression or double compression (dry slugging) tabletting processes (see U.S. Pat No. 3,490,742 issued Jan. 20, 1970 to G. K. Nichols, et al.). The amylose fraction is non-granular because the starch from which it is derived is totally solubilized in order to free the amylose. This material is prepared by gelatinizing the starch and then fractionating high molecular weight (long chain) amylose from the gelatinized starch in water at elevated temperatures. The binder-disintegrant must contain at least 50% of the native (e.g., long chain) amylose which was present in the starch.
U.S. Pat. No. 4,551,177, issued Nov. 5, 1985 to Trubiano, et al. discloses compressible starch, useful as a binder for tablets prepared by direct compression or dry granulation or as a binder-diluent for capsules, which consists essentially of a free-flowing compressible starch powder derived from a cold-water-insoluble, granular starch by treatment with an acid, alkali, and/or alpha-amylase enzyme at a temperature below the gelatinization temperature of the starch, the treated starch being characterized by altered, weakened granules with a less dense interior and disrupted surface, the starch powder effectively binding when compressed.
None of these starch products display all of the desirable binder properties of microcrystalline cellulose in direct compression tabletting. Due to the high cost of microcrystalline cellulose, there is a need for compressible starches which are suitable for use as binders in any tabletting method, especially direct compression, and which are likewise useful as binder-diluents for capsule filling operations. Additionally, a glossy smooth surface is frequently a desirable attribute in tablets and there is a need for a binder which creates such a surface appearance.
It has been found that starch containing greater than about 90% amylopectin, which starch has been highly or partially enzymatically debranched by treatment with an alpha-1,6-D-glucanohydrolase, such as pullulanase or isoamylase, to yield a starch hydrolysate comprising at least 20%, by weight, short chain amylose, is an excellent direct compression tablet binder which provides a glossy, smooth surface to tablets. Additionally, the debranched starch may be selected such that its functional properties are suited for a variety of tablet excipient functions.